Racemic methylphenidate (MPH) is a central nervous system stimulant that has pharmacological activity qualitatively similar to amphetamines and is widely used in the treatment of attention deficient disorder (ADD) and attention-deficient hyperactivity disorder (ADHD) (l-threo isomer shown in FIG. 1). Symptoms of these disorders include distractability and impulsivity; ADHD is further associated with increased activity of the body. MPH has also been used to treat cognitive defects, including dementia, that manifest in at least 70% of HIV-infected individuals who have developed Acquired Immunodeficiency Syndrome (Navia et al. Ann. Neurol. 1986; 19:517-524). Additionally, d-threo-methylphenidate is used to treat hypersomnia (Aoyama et al. Clin. Pharmacol. Ther., 1994; 55:270-276)
Originally MPH was sold pharmaceutically as a mixture of two racemates, 80% dl-erthro and 20% dl-threo. Subsequent studies revealed that the central stimulant activity residues in the threo racemate, and thus the erythro racemate was removed from the pharmaceutical to improve its therapeutic index.
dl-threo-MPH appears to facilitate dopaminergic and noradrenergic transmission (Maxwell et al. J. Pharmacol. Exp. Ther. 1970;173:158-165; Breese et al., Paychopharmacology 1975; 44:5-10; Janowsky et al. Eur. J. Pharmacol. 1985; 108:187-191). Patrick et al. found that d-threo-MPH produced greater induction of locomotor activity in rats and greater inhibition of tritiated dopamine and l-norepinephrine uptake into striatal and hypothalamic synaptosomes, respectively, than the l-isomer (Patrick et al. J. Pharmacol. Exp. Therap. 1987; 241:152-158). Additionally, Srinivas et al. showed that the pharmacodynamic activity of the racemic threo-MPH in treating ADHD resides in the d-threo isomer (Srinivas et al. Clin. Pharmacol. Ther. 1992; 52:561-568). Administration of d-threo-MPH instead of dl-threo-MPH in patients suffering from ADD, ADHD, AIDS cognitive decline, and AIDS Dementia Complex resulted in less severe side effects. These include a reduction in the euphoric effect that is produced when dl-threo-MPH is administered intravenously or through inhalation, to create a potential for substance abuse in patients (U.S. Pat. No. 5,908,850). In rats, baboons, and humans, [.sup.11 C]d-threo-MPH demonstrated highest regional accumulation in the basal ganglia; in contrast, [.sup.11 C]d-threo-MPH displayed similar uptake in all brain regions, suggesting that its distribution in the brain is less specific. This result further supports the hypothesis that the pharmacological specificity of racemic threo-MPH in elevating striatal dopamine concentration resides in the d-threo isomer (Ding et al. Psychopharmacology 1997; 131:71-78; Aoyama et al. Pharm. Res. 1994; 11:407-411).